Huntington disease (HD) is an autosomal dominant disease characterized by premature central nervous system degeneration, primarily in the striatum of medium-sized spiney neurons. HD has a relentless 15-20 year course from onset to death. Age of symptom onset is highly heritable, ranging from ages 3 to 70. Animal models led to the hypothesis that "poor aging genes" result in early HD onset. A test of this hypothesis in 214 families revealed correlations of about 0.5 (P less than 0.001) between HD age of onset and age of death of unaffected first degree relatives but insignificant correlations between age of onset in affected individuals and longevity of their spouses, supporting the "aging gene" hypothesis and making HD age of onset a more powerful predictor of mortality than many currently used biomarkers of aging. Children of mothers with HD have onset of symptoms an average of 3.5 years later than the children of affected fathers, providing a testable hypothesis of a maternal effect that delays neuronal death with aging. We propose a genetic-epidemiological study of adults, who had a parent with HD, to determine which biomarkers of aging, diseases of aging or disease risk factors are related to familial age of onset in HD. This study will further test the hypothesis that HD is a stressor of central nervous system aging, provide insight into the maternal influence that delays the symptoms of neuronal death and measure the effects of neuronal death on biomarkers of aging in the subjects who later have symptoms. Similar hypotheses have been proposed to explain onset of Alzheimer's and Parkinson's diseases. We judge HD especially appropriate to test this family of the brain and well documented families are available from the National HD Research Roster. The fact that the HD gene has been located on the tip of the short arm of chromosome 4 will undoubtedly lead to understanding of its molecular pathology and ease the translation of findings to the understanding of other causes of premature neuronal death.